1. Field of the Invention
The present invention relates generally to a novel use of Troglitazone and related thiazolidinedione derivatives. More specifically, it relates to the use of Troglitazone and related thiazolidinedione derivatives in the treatment of the climacteric. It also relates to
2. Description of Related Art
Troglitazone is a member of a class of antidiabetic drugs termed thiazolidinediones. Although the mechanism is unknown, this class of drugs lowers insulin resistance and improves glucose tolerance (Nolan et al., 1994). For these reasons Troglitazone has found use in the treatment of noninsulin dependent diabetes mellitus (NIDDM)(U.S. Pat. No. 5,478,852) incorporated by reference herein. NIDDM otherwise referred to as Type II diabetes, is the form of diabetes mellitus which occurs predominately in adults in whom adequate production of insulin is available for use, yet a defect exists in insulin-mediated utilization and metabolism of glucose in peripheral tissues. The population with impaired glucose tolerance progresses to NIDDM at a rate of 5% to 10% of cases per year. Failure to treat NIDDM can result in mortality due to cardiovascular disease and other diabetic complications including retinopathy, nephropathy, and peripheral neuropathy. Administration of Troglitazone can provide effective treatment of populations experiencing impaired glucose tolerance and may result in the delay or prevention of the onset of NIDDM.
Moreover, Troglitazone has been further implicated in the treatment of polycystic ovary syndrome PCO). This is a syndrome in women that is characterized by chronic anovulation and hyperandrogenisim. Women with this syndrome often have insulin resistance and an increased risk for the development of noninsulin-dependent diabetes mellitus. In women with PCO given Troglitazone (400 mg every day), insulin resistance was reduced and 2 of the 25 women studied had ovulatory menses (Dunaif et al., 1996).
While advances continue to be made in chemotherapy treatment of cancer, effective agents are still lacking for the treatment many types of cancer. One such type is mesenchymal tumors. The mesenchyma consists of the meshwork of embryogenic connective tissue in the mesoderm from which are formed the connective tissues of the body as well as blood vessels and lymphatic vessels. There are many types of mesenchymal tumors including but nor limited to sarcomas (general), rhabdomyosarcomas, fibrosarcomas, retinoblastoma, hemangiopericytoma, congenital mesoblastic nephroma, and mesotheliomas (Pierce and Figlin, 1992: Odell, 1996: Connelly and Budd, 1996). These types of tumors are aggressive and fast growing, thus development of effective chemotherapeutic agents for their treatment is of particular need.
One mechanism through which thiazolidinediones are believed to have biological effect is their ability to serve as a high affinity ligand for the orphan steroid receptor peroxisome proliferator-activated receptor gamma (PPARxcex3) (Lehmann et al., 1995). PPARxcex3 is a member of the nuclear receptor superfamily of orphan steroid receptors that serve as transcription factors (Motojima, 1993). This family includes receptors for the steroid, thyroid and retinoid hormones. Activation of PPARxcex3 is implicated in adipocyte differentiation through the activation of adipocyte-specific gene expression (Lehmann et al., 1995). This gene expression is mediated through binding to a PPARxcex3 response element (PPRE) in the promoter region of target genes (Forman et al., 1995). This PPRE is composed of a directly repeating core site separated by one nucleotide (NNN-AGGTCA-N-AGGTCA). To bind to a PPRE, PPARxcex3 must form a heterodimer with the 9-cis retinoic acid receptor (RXR). This sequence is classified as a DR-1 consensus sequence that is universal for orphan receptors (Vidal-Puig, 1996). Because of the universal nature of this consensus sequence, other transcription factors can bind to the PPRE and compete with the binding of PPARxcex3. One such transcription factor is COUP-TFII that antagonizes PPAR signaling in mammalian cells (Marcus et al., 1996).
PPARxcex3 is in a family of three orphan receptors that are encoded by different genes Motojima, 1993). The three PPAR genes are PPARxcex1,PPARxcex4, and PPARxcex3 (Motojima, 1993). Moreover, 2 isoforms of PPARxcex3 also exist, PPARxcex31 and PPARxcex32 (Vidal-Puig et al., 1996). These 2 proteins differ only in their NH2-terminal-30 amino acids and are the result of alternative promoter usage and differential mRNA splicing (Vidal-Puig et al., 1996). In addition to thiazolidinediones, another ligand fur the PPARxcex3 nuclear receptor is the arachidonic acid metabolite 15-deoxy-delta12, 14-prostaglandin J2 (15d-PGJ2). This prostaglandin activates PPARxcex3-dependent adipogenesis, but activated PPARxcex1 only at high concentrations (Forman et al., 1995: Kliewer et al., 1995). This is further evidence that the PPAR family subtypes are distinct from one another in their pharmacological response to ligands.
The climacteric is defined as the syndrome of endocrine, somatic and psychological changes occurring at the termination of the reproductive period in the female. The menstrual irregularities are episodes of prolonged menstrual bleeding caused by a loss of ovulation. The loss of ovulation is caused by a failure of development of ovarian follicles. Currently the most common method for treatment to the climacteric is hormone replacement, including administration of birth control pills, oral administration of estrogen and progesterone preparations or oral administration of progesterone only preparations (Shaaban, 1996). While relieving symptoms of the climacteric, these treatments have many associated risks and side effects. Risks associated with hormone treatment include endometrial carcinoma, hypertension, hyperlipidemia, cholelithiasis (gallstones), breast cancer, and deep venous thrombosis (Barentsen, 1996).
Compounds useful for practicing the present invention, and methods of making these compounds are known. Some of these compounds are disclosed in WO 91/07107; WO 92/07838; WO 92/07839; WO92/02520; WO 94/01433; WO 89/08651; JP Kokai 69383 92; U.S. Pat. Nos. 4,287,200; 4,340,605; 4,438,141; 4,444,779; 4,461,902; 4,572,912; 4,687,777; 4,703,052; 4,725,610; 4,873,255; 4,897,393; 4,897,405; 4,918,091; 4,948,900; 5,002,953; 5,061,717; 5,120,754; 5,132,317; 5,194,443; 5,223,522; 5,232,925; and 5,260,445. The disclosure of these publications are incorporated herein by reference in particular with respect to the active compounds disclosed therein, and methods of preparation thereof.
The present invention is the result of the surprising finding that Troglitazone and related thiazolidinedione compounds inhibi-steroidogenesis in granulosa cells. A related aspect of the present invention is the discovery that therapeutic levels of Troglitazone can kill rapidly growing cancerous cells expressing the orphan nuclear receptor PPARxcex3, while not affecting the viability of normal cells. The discovery of these new uses for Troglitazone and related compounds provides important new agents for the treatment of certain types of cancers and for the treatment of the climacteric. The term climacteric is well known in the art as the syndrome of endocrine, somatic and psychological changes occurring at the termination of the reproductive period in the female.
A type of cancer which is particularly likely to be treatable with troglitazone and related thiazolidinedione derivatives are mesenchymal tumors. The mesenchyma consists of the meshwork of embryogenic connective tissue in the mesoderm from which are formed the connective tissues of the body as well as blood vessels and lymphatic vessels. There are many types of mesenchymal tumors including but not limited to sarcomas (general), rhabdomyosarcomas, fibrosarcomas, retinoblastoma, hemangiopericytoma, congenital mesoblastic nephroma, and mesotheliomas.
Studies show that Troglitazone is a ligand for the orphan nuclear receptor PPARxcex3. Translocation of this transcription factor in the nucleus of cells at sufficient rates inhibits transcription and reduces progesterone production in normal granulosa cells without a loss in cell viability. However, this inhibition of transcription in rapidly dividing cancer cells expressing PPARxcex3 results in the loss of cell viability and inhibition of cell growth. The mechanism of PPARxcex3 inhibition of gene transcription most likely results from the competition of the PPARxcex3 transcription factor with the other orphan nuclear factors binding to DR-1 consensus elements on genes and impairing the promoter activity of those elements. The inhibitory effects of Troglitazone on steroidogenesis make it useful for the reduction of menstrual bleeding in women as they develop reduced ovulation as they approach menopause. Because there is no loss of viability in normal cells, but a reduction in rapidly growing cancer cells, Troglitazone and related compounds may also be used in the treatment of cancer, to impair the growth of cancer cells without killing normal cells.
As agents having the aforementioned effects, the compounds of the following formulas are useful in treating individuals.
Accordingly, the present invention is the use of compounds of Formula I 
wherein R1 and R2 are the same or different and each represents a hydrogen atom or a C1-C5 alkyl group:
R3 represents a hydrogen atom, a C1-C6 aliphatic acyl group, an alicyclic acyl group, an aromatic acyl group, a heterocyclic acyl group, an araliphatic acyl group, a (C1-C6 alkoxy)carbonyl group, or an aralkyloxycarbonyl group;
R4 and R5 are the same or different and each represents a hydrogen atom, a C1-C5 alkyl group or a C1-C5 alkoxy group, or R4 and R5 together represent a C1-C5 alkylenedioxy group;
n is 1, 2 or 3;
W represents the xe2x80x94CH2xe2x80x94, CO, or CHxe2x80x94OR6 group (in which R6 represents any one of the atoms or groups defined for R3 and may be the same as or different from R3 and
Y and Z are the same or different and each represents an oxygen atom or an imino (xe2x95x90NH) group;
and pharmaceutically acceptable salts thereof.
The present invention is also the use of compounds of the Formula II 
wherein R11 is substituted or unsubstituted alkyl, alkoxy, cycloalkyl, phenylalkyl, phenyl, aromatic acyl group, a 5- or 6-membered heterocyclic group including 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or a group of the formula 
wherein R13 and R14 are the same or different and each is lower alkyl or R13 and R14 are combined to each other either directly or as interrupted by a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur to form a 5- or 6-membered ring;
wherein R12 means a bond or lower alkylene group; and
wherein L1 and L2 are the same or different and each is hydrogen or lower alkyl or L1 and L2 are combined to form an alkylene group; or a pharmaceutically acceptable salt hereof.
The present invention is also the use of compounds of the Formula III 
wherein R15 and R16 are independently hydrogen, lower alkyl containing 1 to 6 carbon atoms, alkoxy containing 1 to 6 carbon atoms, halogen, ethynyl, nitrile, methylthio, trifluoromethyl, vinyl, nitro, or halogen substituted benzyloxy; n is 0 to 4 and the pharmaceutically acceptable salts thereof.
The present invention is also directed to the use of compounds of the Formula IV 
wherein the dotted line represents a bond or no bond;
V is xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94 or S;
D is CH2, CHOH, CO, Cxe2x95x90NOR1xe2x80x94 or CHxe2x95x90CH;
X is S, O, NR18, xe2x80x94CHxe2x95x90N or xe2x80x94Nxe2x95x90CH;
Y is CH or N;
Z is hydrogen, (C1-C-)alkyl, (C1-C-)cycloalkyl, phenyl, naphthyl, pyridyl, furyl, thienyl, or phenyl momo- or disubstituted with the same or different groups which arc (C1-C3)alkyl, trifluoromethyl, (C1-C3)alkoxy, fluoro, chloro, or bromo;
Z is hydrogen or (C1-C3)alkyl;
R17 and R18 are each independently hydrogen or methyl; and
n is 1, 2, or 3;
the pharmaceutically acceptable cationic salts thereof; and
the pharmaceutically acceptable acid addition salts thereof when the compound contains a basic nitrogen.
The present invention is also directed to the use of compounds of the Formula V 
wherein the dotted line represents a bond or no bond;
A and B are each independently CH or N, with the proviso that when A or B is N, the other is CH;
X1 is S, SO, SO2, CH2, CHOH, or CO;
n is 0 or 1;
Y1 is CHR20 or NR21, with the proviso that when n is 1 and Y1 is NR21, X1 is SO2 or CO;
Z2 is CHR22, CH2CH2, CHxe2x95x90CH, 
xe2x80x83OCH2, SCH2, SOCH2 or SO2CH2;
R19, R20, R21, and R22 are each independently hydrogen or methyl; and
X2 and X3 are each independently hydrogen, methyl, trifluoromethyl, phenyl, benzyl, hydroxy, methoxy, phenoxy, benzyloxy, bromo, chloro, or fluoro;
a pharmaceutically acceptable cationic salt thereof; or
a pharmaceutically acceptable acid addition salt thereof when A or B is N.
The present invention also relates to the use of compounds of the Formula VI 
or a pharmaceutically acceptable salt thereof wherein R23 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or mono- or di-substituted phenyl wherein said substituents are independently alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen, or trifluoromethyl.
The present invention also provides the use of a compound of Formula VII 
or a tautomeric form thereof and or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein:
A2 represents an alkyl group, a substituted or unsubstituted aryl group, or an aralkyl group wherein the alkylene or the aryl moiety may be substituted or unsubstituted;
A3 represents a benzene ring having in total up to 3 optional substituents:
R24 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group wherein the alkyl or the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group; or A2 together with R24 represents substituted or unsubstituted C2-3 polymethylene group, optional substituents for the polymethylene group being selected from alkyl or aryl or adjacent substituents together with the methylene carbon atoms to which they are attached form a substituted or unsubstituted phenylene group;
R25 and R26 each represent hydrogen, or R25 and R26 together represent a bond;
X4 represents O or S; and
n represents an integer in the range from 2 to 6.
The present invention also provides the use of a compound of Formula VIII 
or a tautomeric form thereof and or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof wherein:
R27 and R28 each independently represent an alkyl group, a substituted or unsubstituted aryl group, or an aralkyl group being substituted or unsubstituted in the aryl or alkyl moiety; or R27 together with R28 represents a linking group, the linking group consisting of an optionally substituted methylene group or an O or S atom, optional substituents for the said methylene groups being selected from alkyl-, aryl, or aralkyl, or substituents of adjacent methylene groups together with the carbon atoms to which they are attached form a substituted or unsubstituted phenylene group;
R29 and R30 each represent hydrogen, or R29 and R30 together represent a bond;
A4 represents a benzene ring having in total up to 3 optional substituents;
X5 represents O or S; and
n represents an integer in the range from 2 to 6.
The present invention also provides the use of a compound of Formula IX 
or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein:
A5 represents a substituted or unsubstituted aromatic heterocyclyl group;
A6 represents a benzene ring having in total up to 5 substituents
X6 represents O, S, or NR32 wherein R32 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;
Y2 represents O or S;
R31 represents an alkyl, aralkyl, or aryl group; and
n represents an integer in the range from 2 to 6.
Suitable aromatic heterocyclyl groups include substituted or unsubstituted, single or fused ring aromatic heterocyclyl groups comprising up to 4 hetero atoms in each ring selected from oxygen, sulfur, or nitrogen.
Favored aromatic heterocyclyl groups include substituted or unsubstituted single ring aromatic heterocyclyl groups having 4 to 7 ring atoms, preferably 5 or 6 ring atoms.
In particular, the aromatic heterocyclyl group comprises 1, 2, or 3 heteroatoms, especially 1 or 2, selected from oxygen, sulfur, or nitrogen.
Suitable values for A5 when it represents a 5-membered aromatic heterocyclyl group include thiazolyl and oxazoyl, especially oxazoyl.
Suitable values for A6 when it represents a 6-membered aromatic heterocyclyl group include pyridyl or pyrimidinyl. 
Suitable R31 represents an alkyl group, in particular a C1-6 alkyl group, for example a methyl group. Preferably, A5 represents a moiety of formula (a), (b), or (c);
Formula (a), (b) and (c)
wherein:
R33 and R34 each independently represents a hydrogen atom, an alkyl group, or a substituted or unsubstituted aryl group or when R33 and R34 are each attached to adjacent carbon atoms, then R33 and R34 together with the carbon atoms to which they are attached form a benzene ring wherein each carbon atom represented by R33 and R34 together may be substituted or unsubstituted; and in the moiety of Formula(a). X7 represents oxygen or sulfur.
In one favored aspect R33 and R34 together represent a moiety of Formula (d): 
wherein R35 and R36 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl, or alkoxy.
The present invention also provides for the use of compounds for Formula X 
or a tautomeric form thereof and or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof wherein:
A7 represents a substituted or unsubstituted aryl group;
A8 represents a benzene ring having in total up to 5 substituents;
X8 represents O, S, or NR39 wherein R39 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;
Y3 represents O or S;
R37 represents hydrogen;
R38 represents hydrogen or an alkyl, aralkyl, or aryl group or R37 together with R38 represents a bond; and
n represents an integer in the range from 2 to 6.
The present invention is also directed to the use of compounds of Formula XI 
or a tautomeric form thereof and or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, wherein:
A1 represents a substituted or unsubstituted aromatic heterocyclyl group;
R1 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;
A2 represents a benzene ring having in total up to 5 substituents; and
n represents an integer in the range of from 2 to 6.
Suitable aromatic heterocyclyl groups include substituted or unsubstituted, single or fused ring aromatic heterocyclyl groups comprising up to 4 hetero atoms in each ring selected from oxygen, sulfur, or nitrogen.
Favored aromatic heterocyclyl groups include substituted or unsubstituted single ring aromatic heterocyclyl groups having 4 to 7 ring atoms, preferably 5 or 6 ring atoms.
In particular, the aromatic heterocyclyl group comprises 1, 2, or 3 heteroatoms, especially 1 or 2, selected from oxygen, sulfur, or nitrogen.
Suitable values for A1 when it represents a 5-membered aromatic heterocyclyl group include thiazolyl and oxazolyl, especially oxazoyl.
Suitable values for A1 when it represents a 6-membered aromatic heterocyclyl group include pyridyl or pyrimidinyl.
Preferably, A5 represents a moiety of formula (a), (b), or (c): 
wherein:
R4 and R5 each independently represents a hydrogen atom, an alkyl group, or a substituted or unsubstituted aryl group or when R4 and R5 are each attached to adjacent carbon atoms, then R4 and R5 together with the carbon atoms to which they are attached form a benzene ring wherein each carbon atom represented by R4 and R5 together may be substituted or unsubstituted; and in the moiety of formula (a), X represents oxygen or sulfur.
The present invention is also directed to the use of compounds of Formulas XII and XIII. 
or a pharmaceutically acceptable salt thereof wherein the dotted line represents a bond or no bond:
R is cycloalkyl of three to seven carbon atoms, naphthyl, thienyl, furyl, phenyl or substituted phenyl wherein said substituent is alkyl of one to three carbon atoms, alkoxy of one to three carbon atoms, trifluoromethyl, chloro, fluoro or bis(trifluoromethyl);
R1 is alkyl of one to three carbon atoms;
X is O or Cxe2x95x90O;
A is O or S; and
B is N or CH.
In one aspect the present invention is the use the compounds of Formulas I through Formula XIII, and Formulas Ia, lb and Ic, for the treatment of the climacteric and of cancer. These compounds are herein referred to as thiazolidine derivatives. Where appropriate, the specific names of thiazolidine derivatives may be used including: Troglitazone, cioglitazone, pioglitazone and BRL 49653.
A preferred group of compounds are those of Formula XII wherein the dotted line represents no bond, R1 is methyl, X is O and A is O. Especially preferred within this group are the compounds where R is phenyl, 2-naphthyl and 3.5-bis(trifluoromethyl)phenyl.
Another group of preferred compounds are those of Formula XIII wherein the dotted line represents no bond. R1 is methyl and A is O. Especially preferred within this group are the compounds where B is CH and R is phenol, p-tolyl, m-tolyl, cyclohexyl, and 2-naphthyl. Also especially preferred is the compound where B is N and R is phenyl.
A still further embodiment of the present invention is the use of a pharmaceutical composition for administering an effective amount of a compound of the preceding Formulas I through XIII along with a pharmaceutically acceptable carrier in unit dosage form in the treatment methods mentioned above.